Lecture 4
Adaptive immunity:
T and B cell development
HLSC 4806
Lisa Kalischuk-Tymensen
Summary – T cells and antigen
recognition
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•
TCRs recognize antigen that is presented by MHC
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–
–
APCs MUST present antigen to T cells
TCRs recognize both MHC and the peptide
TCR diversity....3 processes that contribute
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•
•
MHC
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–
Combinatorial V(D)J joining of various germ-encoded DNA
segments
Combinations of different α and β chains
Junctional flexibility
MHC class I and II, present peptide fragments to T cells
(CD8+ Cytotoxic T lymphocytes or CD4+ Helper T cells)
MHC class I is found on most nucleated cells, whereas MHC
class II is found primarily on APCs
MHC diversity ....germline encoded, only 6 genes, but can
bind many peptides (degeneracy)
1
Antigen recognition:
a problem of diversity
V
• Each BCR/antibody
or TCR receptor
binds ONE specific
antigen
• Require ~ 100 million
different TCR or
antibodies for
protection !!!
• Human genome: only
25 000 genes
V
D
J
V
J
D
J
C
J
V
C
C
C
Antibody
CD3
V
J
C
V D J C
T cell
TCR
Genetic basis for receptor
generation
• Generation of a vast array of BCRs/antibodies
and TCRs is accomplished by recombination of
various V, (D), and J gene segments encoded
in the germline. Other processes also
contribute to the diversity of
BCRs/antibodies and TCRs (see lecture 3).
• The receptors on different B cells and T cells
are so diverse, that collectively, our
lymphocytes can recognize most pathogens.
2
Antigen recognition
• Problem: If diversity then how to
discriminate ‘self’ from ‘non-self’
• Solution: deletion of self-reactive
lymphocytes
• Tolerance (lecture 11a)
• Malfunction:
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Immunodeficiency (lecture 10)
Autoimmune diseases (‘self’ from ‘non-self’; lecture 11)
IBD (‘extended-self’ from ‘non-self’; lecture 12)
Cancer (‘altered-self’ from ‘non-self’)
The thymus is the site
of T cell development
• Importance of thymus
in immunity
– DiGeorge’s syndrome
(humans) and nude mice
• Thymus absent
• Severe immunodeficiency
• No T cells
– Have B cells but no
antibodies (since no
helper T cells)
• T cell = thymusdependent lymphocyte
3
The aging thymus
• Fully developed at birth
• Production of mature T cells
within the thymus is greatest
at puberty
• Thymus shrinks with
age....production of new T
cells declines with age
– Removal of thymus after
puberty does not cause notable
loss of T cell function
– Once T cell repertoire is
established, immunity is
sustained without production of
new T cells; the pool of
peripheral T cells is maintained
by proliferation of mature T
cells
Figure 2-13 KUBY
Stages of T cell development
1.
2.
1.
2.
3.
4.
3.
4.
T cell progentiors originate in the bone marrow
(hematopoietic stem cells) and migrate to thymus
Mature in the thymus: “thymic education”
Mature naïve T cells migrate to peripheral lymphoid
organs (lymph nodes, spleen, Peyer’s patches)
Activated T cells (effector T cells) proliferate and
migrate to sites of inflammation
4
T cells must undergo numerous steps in the thymus to
develop from T cell progenitors to mature T cells
Cytotoxic T cell (CD8+)
Helper T cell (CD4+)
MHC I
Endogenous
Antigen
MHC I
Endogenous
Antigen
MHC II
Exogenous
Antigen
CD4
CD8
CD3
CD3
CD3
2 main types of mature T cells:
(DC, activated MΦ, activated B cell)
• cytotoxic T lymphocytes (CD8+)
• helper T cells (CD4+)
“target cell”
T cells progenitors
DO NOT express
TCR, CD3, CD4 and
CD8 receptors
4 main events:
• Proliferation of cells
within bone marrow
• Rearrangement of
TCR (lecture 3)
• Changes in cell
surface markers
(CD3, CD4, CD8)
• +ve and -ve
selection (“thymic
education”)
Figure 10-2 KUBY
5
Thymic education
• The antigenic diversity of T cells is reduced
during maturation in the thymus by a selection
process (“thymic eduction”) that allows only
MHC-restricted and nonself-reactive T cells
to mature.
• T cells selection processes include positive
and negative selection in the thymus.
• Finally mature T cells (CD4+ that recognize
MHCII and CD8+ that recognize MHCI) exit
thymus.
The thymus
• Thymic cortex: outer
cortical region
• Thymic medulla: inner
region
• Thymic stroma: network
of epithelial cells
– Cortical epithelial cells
– Medullary epithelial cells
• Thymic dendritic cells
(these are different
from peripheral DCs)
and macrophages
6
Thymic education: positive
selection
• Takes place in the
CORTEX of the thymus
• Thought that T cells
which recognize self
MHC receive “survival”
signals from thymic
epithelial cells and are
positively selected
• Cells that fail positive
selection are eliminated
by apoptosis
Thymic education: negative
selection
• Takes place in the
MEDULLA of the thymus
• T cells which demonstrate
too high an affinity for self
MHC molecules alone or
self antigen presented by
self-MHC are “deleted” in
the medulla by thymic
dendritic cells and
macrophages
7
Thymic education
+ selection
- selection
Thymic education
Positive selection
ensures
MHC restriction
Ensures that ALL mature
T cells will have TCRs
that recognize antigen
presented by MHC
molecules (i.e., can be
activated)
Negative selection
ensures
self-tolerance
8
Thymic education
Positive selection
ensures
MHC restriction
Ensures that ALL mature
T cells will have TCRs
that recognize antigen
presented by MHC
molecules (i.e., can be
activated)
Negative selection
ensures
self-tolerance
Most developing T cells die in the thymus
Paradox of positive and negative
selection
• Hypothesis
– Positive selection (survival) of T cells
results from a relatively WEAK interaction
between TCRs and MHC-self peptide
displayed on cortical thymic epithelial cells
– Negative selection (death) of T cells is
induced by a STRONG interaction between
TCRs and MHC-self peptide expressed on
thymic dendritic cells plus macrophages
and/or medullary thymic epithelial cells
9
Summary of T cell development
• Migration of T cell progenitors (from stem
cells - hematopoiesis) in the bone marrow to
the thymus
• Proliferation of thymocytes in the thymus
• Rearrangement of TCR, expression of T cell
specific surface molecules, and positive and
negative selection (“thymic education”),
• Finally mature T cells (CD4+ that recognize
MHCII and CD8+ that recognize MHCI) exit
thymus and migrate to peripheral lymphoid
organs (lymph nodes, spleen, Peyer’s patches)
Summary of T cell development
• Once T lymphocytes leave the thymus, they are
carried in blood to peripheral lymphoid organs (i.e.,
MLNs, spleen, PPs)
– Guided by ‘signals’ to correct location (i.e., homing)
– Cytokines and chemokines
• If do not encounter antigen, then leave and recirculate
via lymph and blood, continually re-entering lymphoid
organs until antigen is encountered (Lecture 5a –
lymphocyte trafficking)
• It the T cell encounters its cognate antigen (APCs)
within the lymphoid organs...activated T cell
proliferates and differentiates (clonal expansion) into
effector T cells such as cytotoxic T lymphocytes and
helper T cells (Lecture 5b, 6a)
10
B cell development
• B cells originate in the bone
marrow where they also undergo
V(D)J gene recombination
• Exit as mature but naïve B cell
(expressing IgM) into the
bloodstream and lymph
• Naïve B cells migrate to
peripheral lymphoid organs
(lymph nodes, spleen, Peyer’s
patches) where they are
activated
• Activated B cells proliferate and
differentiate into plasma or
memory cells .....generally remain
in the lymphoid organ or migrate
back to bone marrow (the
antibodies do the traveling)
Figure 11-1 KUBY
Self-reactive B cells are deleted
in the bone marrow
• Deletion of self-reactive B cells occurs in the bone marrow.
• Once new B cells rearrange their B cell receptors, they are
“tested” to see if these receptors recognize self antigens that
are present in the bone marrow. If they do, the the B cell is
given another chance to rearrange its light chain to make an new
chain that doesn’t recognize self antigen (this is called “receptor
editing”).
• Only ~10% of all B cells pass this test – the rest die by
apoptosis in the bone marrow.
• Those B cells that do not recognize self-antigens are released
from the bone marrow to circulate in the blood and lymph
11
Summary: Stages of B cell development
1.
1.
2.
3.
4.
2.
3.
4.
B cell progentiors originate in the bone marrow
(hematopoietic stem cells) and rearrange their Ig genes.
Undergo negative selection in the bone marrow
Mature naïve B cells migrate to peripheral lymphoid organs
(lymph nodes, spleen, Peyer’s patches)
Activated B cells differentiate (plasma cells) and
proliferate, remain in lymphoid organs or and migrate to
the bone marrow, and secrete antibodies.
Mature naïve lymphocytes migrate to the
peripheral lymphatic organs such as lymph nodes
12
Summary of B cell clonal selection and expansion
B cell progenitors in bone marrow
B cells with rearranged BCRs
Removal of selfreactive B cells
Antigen
recognition
Proliferation &
differentiation
(clonal expansion)
Effector activity (antibodies)
Summary:
clonal selection hypothesis
1.
2.
3.
4.
Each B or T lymphocyte bears a single type of
receptor with a unique specificity
Interaction of a lymphocyte receptor (BCR or TCR)
with its cognate antigen leads to lymphocyte
activation (lymphocyte proliferation and
differentiation)
The effector T cells will bear identical receptors to
those of the parent cell from which the effector
cell was derived
Self-reactive lymphocytes are deleted at an early
stage of development and therefore generally
absent from the repertoire of mature lymphocytes
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